It is now well established that the addiction experienced by smokers is due to the nicotine present in the tobacco. Nicotine produces a myriad of profound behavioral and physiological effects. It is acutely rewarding, which promotes repeated drug administration and could lead to dependence in vulnerable individuals. Nicotine reinforces self-administration and reinforces place preference in animals. In addition, cessation of chronic exposure to nicotine results in withdrawal that consists of somatic and affective components. The long-range goal of the proposed research is to develop potential treatment medications for nicotine addiction. Our first strategy is to develop partial agonists and antagonists that act at the orthosteric site of nicotinic receptors. Our progress to date has demonstrated that epibatidine analogs hold great promise in that specific structural modifications have resulted in analogs with extremely high affinity for receptors labeled with [3H]epibatidine but with varying degrees of efficacy. Our second strategy is to develop negative allosteric modulators for nicotinic receptors that may provide a pharmacological profile different from that of orthosteric ligands. Our discovery that ligands for the PCP (non-NMDA) second site acted as negative allosteric modulators at nicotinic receptors served as the basis for proposing a synthetic and evaluation program for hexahydroindeno[1,2]pyrrole, tetrahydro-2,5-methano-2H-benzazepine, and tetrahydro-2,5-methano-1H-2- benzazepine analogs. The hypothesis of this project is that a successful smoking cessation pharmacotherapy would at least include partial activating or blocking action (direct or indirect) at orthosteric synthetic program is to develop analogs with a wide range of efficacies to include partial agonists to pure antagonists. Our general approach will be to synthesize and evaluate the epibatidine analogs for their ability to compete with [3H]epibatidine ( brain. Analogs meeting criteria will be evaluated in vivo in a mouse model (acute agonist and antagonist properties), and those that exhibit specific criteria will be evaluated further in physical withdrawal and reward models (conditioned place preference and self-administration). Plans are underway to begin testing analogs already identified as lead compounds in rat self-administration. Analogs of interest will be evaluated in oocytes for receptor efficacy and selectivity at various nAChRs. A slightly modified approach will be required for the allosteric modulators since they will not compete directly with [3H]epibatidine and [125I]iodo-MLA binding. Rather, they will be evaluated initially for their ability to alter ACh effects in oocytes containing 42, 34, and 7 nAChRs. Those that are identified as negative modulators will be candidates for in vivo evaluation. PUBLIC HEALTH RELEVANCE: In 2004, an estimated 46 million Americans were cigarette smokers. Even though most smokers want to quit, only about 3% can do so without the use of other intervention. Since smoking is associated with cancer, cardiovascular disease, cerebral vascular disease, chronic obstructive airway disease, and pregnancy complications, development of new and better pharmacotherapies to treat smokers would be tremendously beneficial to society. This application addresses this problem by proposing studies to develop competitive antagonists and partial agonists as well as allosteric modulators of nicotinic acetylcholine receptors as new pharmacotherapies to treat smokers.